The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, 560 First Avenue, New York, NY 10016, U.S.A.
Anticancer Res. 2011 Oct;31(10):3259-65.
Most metastatic melanomas are refractory to current available therapy, underscoring the need to identify new effective treatments. Sorafenib, a multikinase inhibitor of the mitogen-activated protein kinase signaling pathway, showed promise in earlier stages of clinical development, but ultimately failed to demonstrate efficacy as a single agent in the treatment of melanoma. In order to enhance the efficacy of sorafenib in the treatment of melanoma, we tested over 2,000 naturally occurring compounds and marketed drugs in the presence of sorafenib in chemoresistant human melanoma cell lines also resistant to sorafenib-induced apoptosis. Of the 9 compounds identified as sorafenib sensitizers, we prioritized the cholesterol-lowering agent fluvastatin, based on its favorable pharmacokinetics and safety profile. Our results demonstrate that fluvastatin at 1 μM, a level safely achieved through oral administration, dramatically enhances the growth-inhibitory activity of clinically achievable concentrations of sorafenib in M14 and SKM-173 melanoma cells, with a 3.2- and 3.6-fold reduction in sorafenib 50% growth inhibition (GI50), respectively. Similar effects were observed for other melanoma cell lines. Combination indices analysis revealed a synergistic relationship between the two agents. Fluvastatin enhances sorafenib-mediated apoptosis as revealed through enhanced cleavage of poly (ADP-ribose) polymerase. In combination with sorafenib, fluvastatin treatment results in reduced levels of activated murine thymoma viral oncogene homolog along with enhanced levels of activated c-Jun N-terminal kinase. Sensitization to sorafenib is unique to fluvastatin, as other statins (pravastatin and simvastatin) do not enhance sorafenib-mediated growth inhibition. These promising results warrant further investigation into the clinical applicability of fluvastatin as an agent for enhancing the efficacy of sorafenib in the treatment of melanoma.
大多数转移性黑色素瘤对目前可用的治疗方法具有抗性，这凸显了需要确定新的有效治疗方法。索拉非尼是一种丝裂原活化蛋白激酶信号通路的多激酶抑制剂，在临床开发的早期阶段表现出了前景，但最终未能证明其作为单一药物在治疗黑色素瘤方面的疗效。为了提高索拉非尼在治疗黑色素瘤方面的疗效，我们在对索拉非尼耐药的人黑色素瘤细胞系中，在存在索拉非尼的情况下测试了超过 2000 种天然存在的化合物和市售药物，这些细胞系也对索拉非尼诱导的细胞凋亡具有抗性。在所鉴定的 9 种索拉非尼增敏化合物中，我们根据其良好的药代动力学和安全性概况，优先选择了降胆固醇药物氟伐他汀。我们的结果表明，氟伐他汀在 1 μM 时（通过口服途径安全达到的水平），可显著增强 M14 和 SKM-173 黑色素瘤细胞中临床可达到的索拉非尼浓度的生长抑制活性，使索拉非尼 50%生长抑制（GI50）分别降低了 3.2 倍和 3.6 倍。其他黑色素瘤细胞系也观察到了类似的效果。组合指数分析显示两种药物之间存在协同关系。氟伐他汀通过增强多聚（ADP-核糖）聚合酶的切割来增强索拉非尼介导的细胞凋亡。与索拉非尼联合使用时，氟伐他汀治疗导致激活的鼠胸腺瘤病毒癌基因同源物水平降低，同时激活的 c-Jun N-末端激酶水平升高。索拉非尼的增敏作用是氟伐他汀特有的，因为其他他汀类药物（普伐他汀和辛伐他汀）不能增强索拉非尼介导的生长抑制作用。这些有希望的结果证明，进一步研究氟伐他汀作为增强索拉非尼在治疗黑色素瘤方面疗效的药物的临床适用性是合理的。
